Pharmacological approaches for diabetes management has expanded from the use of metformin as a first-line agent to implementing newer agents with unique mechanisms of actions; with the goal of obtaining optimal glycemic control. Various studies have looked at different treatment modalities and health outcomes with the newer antidiabetic agents. The sodium-glucose cotransporter inhibitors (SGLT2 is) have provided great evidence for their use. Clinical trials have demonstrated benefits that go beyond their glucose-lowering properties. SGLT-2 inhibitors have shown to decrease blood pressure and provide weight reduction benefits when used in conjunction with other medications. Because SGLT-2 inhibitors do not work in an insulin-dependent manner, these agents can be incorporated with other agents like metformin for management of hyperglycemia. Ertugliflozin, a highly selective SGLT2 inhibitor is being investigated in various clinical trials in order to further expand its role in diabetes management.

In a clinical trial conducted last year by N.B. Amin and colleagues at Pfizer, it was seen that ertugliflozin provided significant improvements in HbA1c, fasting plasma glucose, and body weight when compared to sitagliptin and placebo. Sitagliptin provided similar A1c reductions and fasting blood glucose reductions, however, it did not provide any effect on blood pressure as opposed to ertugliflozin alone.

Merck has been expanding on the use and benefits of this novel SGLT-2 inhibitor. In the VERTIS Factorial study, the effects of ertugliflozin on A1c and fasting glucose levels were further analyzed. This study was a randomized, double-blind clinical trial where 1,233 patients with a diagnosis of type 2 diabetes were randomized to five different treatment arms in order to see the effects of this SGLT-2 inhibitor on glucose control during a 26-week period. The secondary endpoints of the study included the following: HbA1c goal of less than 7%, reductions in fasting plasma glucose, and reductions in body weight and blood pressure, specifically systolic blood pressure. Patients were included in the study if they were uncontrolled with a metformin-only regimen and had eGFR of > 60mL/min/1.73m2. After randomization, patients were assigned to the following groups: ertugliflozin 5 mg plus sitagliptin 100 mg, ertugliflozin 15 mg and sitagliptin 100 mg, ertugliflozin 5 mg alone, ertugliflozin 15 mg alone, or sitagliptin 100 mg alone.

Results from the study showed greater reductions in fasting blood glucose with ertugliflozin 15 mg plus sitagliptin 100 mg, when compared to each individual treatment (p<0.001). Patients taking ertugliflozin 15 mg experienced the most weight reduction (8.1 lbs) when compared to the other treatment groups. Those patients receiving dual therapy with ertugliflozin 15 mg and sitagliptin 100 mg experienced a weight reduction of 6.4 lbs. Additionally, blood pressure reductions were seen across all treatment arms. A 3.4 mmHg decrease was observed in those patients who received ertugliflozin 5 mg and sitagliptin 100 mg (p=0.005 vs. sitagliptin) and 3.7 mmHg decrease in those patients who received ertugliflozin 15 mg plus sitagliptin 100 mg (p=0.002 vs. sitagliptin). The incidence of adverse events was similar across all groups, with the most common adverse event being genital fungal infections predominantly in women (4.9-7.6% vs 2.4-4.7% in men).

These ongoing research efforts highlight the benefits of using this highly selective SGLT-2 inhibitor. With these recent advances and the ongoing efforts to explore the cardiovascular effects of this agent, Merck and Pfizer are looking to submit a New Drug Application by the end of 2016 for ertugliflozin monotherapy and in a fixed-dose combination with sitagliptin (Januvia) and metformin. The ongoing cardiovascular outcomes trial is focusing on obtaining more information about the risk versus benefits of ertugliflozin, Including the risk of cardiovascular death and hospitalization due to CV complications. Results from the VERTIS Factorial suggests that with ertugliflozin, when used alone or in combination, clinically significant blood glucose reductions can be obtained. Similar results were obtained in the VERTIS mono trial where ertugliflozin monotherapy provided significant reductions in fasting plasma glucose, postprandial glucose, body weight, and systolic blood pressure.

Practice Pearls:

Use of SGLT-2 inhibitors in conjunction with metformin, sitagliptin, and other agents provides adequate glycemic control in patients with type 2 diabetes.

Ertugliflozin is a novel highly selective SGLT-2 inhibitor that has shown to provide reductions in fasting blood glucose, A1c, weight, and blood pressure.